DESCRIPTION: The goals of the proposed research are to investigate how upstream platelet-agonist interactions affect the downstream platelet interactions with blood-contacting biomaterials. Almost all past research efforts in the field of biomaterial hem compatibility have focused on the local biomaterial surface properties. While these observations are essential for predicting a material's behavior in circulation, they do not reflect the whole story. For example, upstream suturing of a vascular graft creates an anastomosis (a surgical connection between biomaterial and native blood vessel) that has the potential to transiently expose different agonists to circulating platelets. Our preliminary experiments and mathematical modeling suggest that this upstream history of platelet-agonist interaction significantly influences plateet behavior downstream of an anastomotic site. The upstream priming effects are compounded by the fact that no blood-contacting biomaterials are perfectly hem compatible. It is hypothesized here that the magnitude of the downstream biomaterial-platelet interactions is strongly influenced by the transient platelet exposure to upstream platelet agonists that can prime platelets for adhesion and activation. Platelets exposed to agonists are thus more likely to adhere to and become activated by a downstream biomaterial than in the absence of such agonists. It is not known how far downstream these priming effects persist, how much time is required for the primed platelets to become quiescent again, and by which mechanism this phenomenon takes place. From a biomaterials point of view, this problem translates into determining the acceptable tolerance for the extent of upstream priming. In other words, even biomaterials that have very little tendency to activate platelets may do so simply because of the upstream priming of platelets. The proposed study of upstream platelet-agonist effects is expected to result in a new paradigm in the field of biomaterial-derived platelet aggregation and thrombus growth; one that is not exclusively dependent on the local biomaterial surface properties but includes upstream anastomoses and perturbed blood flow. The combination of experiments and modeling in the proposed study will provide new insight into the roles of different upstream agonists and thus has the potential for establishing predictive parameters that could be used to improve the design of blood contacting devices such as catheters, grafts, and other vascular implants.